3-thioethers of androstene-3-one-17-ols and process of making same



Patented Jan. 27, 1948 '7 UNITED STATES PATENT OFFICE 3-THIOETHERS F ANDROSTENE-S-ONE-l'l- ()LS AND PROCESS OF MAKING SAME Karl Miescher, Riehen, Switzerland, assignor to Ciba Pharmaceutical Products, Incorporated, Summit, N. J a corporation No Drawing. Application July 1, 1942, Serial No. 449,343. In Switzerland January 16, 1941 Section 1, Public Law 690, August 8, 1946 Patent expires January 16, 1961 a final oxidation has proved to be unsatisfactory.

According to patent application Serial No. 306,184 filed November 25, 1939, now Patent No. 2,344,997, dated March 28, 1944, it was found that this operation could be avoided if metallo-organic compounds, for example of the Grignard type or acetylenides, were allowed to react on 3-enolates or B-acetals of saturated and unsaturated androstandiones and, if required, the derivatives thus obtained were treated with hydrolyzing agents.

Further experiments have now shown that it is advantageous to make u e of the corresponding thio-derivativesthe thio-enolates or thioacetals (mercaptols)-in place of the enolates or acetals in the latter process, that is to say, it has been found that the splitting of the enol or acetal compounds-even if occurring to a small extent-is practically completely avoided by making use of these thio-derivatives.

As parent materials, us may be made of thio compounds, 1. e. thioenol ethers or mercaptols, derived from saturated or unsaturated androstanediones or their derivatives, which can containalkyl, such as methyl or ethyl, alkylene, such as ethylene or trimethylene, or even cycloalkyl, aralkyl or aryl radicals, for example, a benzene radical. The preparation of the parent substances from the free ketones takes place in a manner of itself known, for example, by the action of the corresponding mercaptans in the presence of anhydrous acid agents.

Suitable metallo-organic compounds are, for example, the alkali or heavy metal salts of acetylen or its mono-substituted derivatives, aryl-, aralkyland alkyl-alkali compounds, organomagnesium compounds, such as methyl-, ethyl-, allyl-, aralkylor aryl-magnesium halides, acetylene magnesium halides, zinc-alkyl-compounds, etc.

The thio-derivatives thus obtained may be decomposed, if desired, to the free ketones in a manner of itself known, for example, by means 2 of mineral acids, acid anhydrides, cadmium carbonate and mercury salts and the like.

The following examples illustrate the invention:

Example 1 2.9 grams of B-ethyl-thioenol ether of A androstene-3 17-dione (obtained, for example. by heating a mixture of androstenedione and ethyl mercaptan in the presence of paratoluene sulfonic acid, removal of the water formed by the which may have been formed are removed byfiltration. To this filtrate is added an aqueous solution of ammonium chloride; the ethereal layer is removed, dried and evaporated. In this way, a residue consisting of the 3-ethyl-thioenol ether of 17-ethinyl-testosterone is obtained; this may be converted into the known I'I-ethinyl-testosteroneby acid decomposition, for example, by

means of mineral acids.

In place of the 3-ethyl-thioenol ether of A androstene-3:17-dione, other thioenol ethers,- such as methyl-, ethyleneor benzyl-thioenol ethers, may be used as parent substances. The

corresponding mercaptols may also be used asstarting materials for the reaction.

Other unsaturated radicals, for example, the

allyl radical, may be introduced in place of the acetylene radical in an analogous manner.

If B-thio-derivatives of androstandione be used as parent substances, the corresponding l'l-substituted dihydro-testosterones may be obtained.

Example 2 A solution of 2.9 grams of androstenedione-3- ethylene mercaptol in toluene is dropped into an ethereal solution of 3.6 grams of methyl magnesium bromide. (The mercaptol may be obtained, for example, by allowing androstenedione to stand with ethylene mercaptan in the presence of dry hydrogen chloride, diluting the reaction mixture with much ether, treatment of the solution with aqueous potash solution in the presence of ice followed by dilute caustic soda solution and ice, drying the ethereal solution with sodium sulphate, evaporation of dryness, chromatographing the residue with aluminum oxide, and recrystallization from ether.) The reaction mixture is then boiled for a time, after which it is worked up as described in Example 1. In this manner, the 3-ethylene mercaptol of 17- methyl-testosteron is obtained. To eliminate the mercaptol radical, 0.1 gram of the mercaptol is dissolved in 20 ccs. of acetone, a solution (tic-.3 ram of sublimate in 200 cos. of acetone is added together with 0.5 gram of freshly precipitated cadmium carbonate, and the reaction mixture is boiled for 3 to 4 hours under reflux. It is then filtered, the filter being washed with acetone, and I the filtrate is evaporated to dryness in vacuo. Water is added to th residue and the solution is extracted with ether. In order to remove any sublimate that has been transferred to the ;ethereal solution, the latter is washed several times with sodium carbonate, followed by water. After drying and evaporating the free l'l-meth'yl-testosterone is obtained.

Other alkyl groups, such as the ethyl radical, may be introduced in place of the methyl radical.

Ina similar manner, for example, l'7-methyldihydro testosterone may be obtained, in which case, for exampla'other polymethyle'ne mercaptols or diethylor dimethyl-mercaptol may be used as parent substance in place of ethylene mercaptol. In-each case, small quantities of the alcohols, epimer'ic in the 17-position, may be obtained from the mother liquor.

Example 3 2.4 grams of potassium are dissolved in 50 cos. of amylene hydrate; to this solution a benzene solution of 2.6 grams of androstenedione-Ii-ethylthioenol ether is added and acetylene is introduced whilst cooling. When the reaction is ended, the reaction mixture is worked up in the usual manner. In this way, the S-ethyl-thioenol ether of l7-ethinyl-testosterone is obtained. By elimihating the mercaptol bond in a manner of itself known, the known l7-ethinyl-testosterone may be obtained.

The condensation may be carried out, for example, by means of an alkali metal dissolved in liquidammonia instead of by means of potassium in the presence of amylene hydrate.

What I claim is:

1. In a process for the manufacture of a memberof the group consisting of the S-thioenol ethersand'3-thioacetals of the saturated and unsaturated androstane 3-one l7-ols containing a hydrocarbon radical in l'l position, the step of reacting a metallo-organic compound with a member of the group consisting of the 3-thioenol ethers and 3=thioacetals of the saturated and unsaturated androstandiones.

2. A process for the manufacture or a member of the "group consisting of the B-thioenol ethers and 3=thioaceta1sof the saturated and unsaturated androstane-B-one-l'I-ols containing a hydrocarbon radical in 17-position, which comprises reacting a metallo-crganic compound with a member of the group consisting of the 3-thioenol ethers and 3-thioacetals of the saturated and unsaturated androstandiones, and then hydrolyzing the resultant thiocompound.

3. A process for the manufacture of a member of the group c'on'sisting or the S-thioenol ethers and 3-thioacet'als of the saturated and unsaturated androstane-3-one-17-ols containing hydrocarbon radical in 17-position, which comprises reacting a saturated metallo-organic compound with a member of the group consisting of the 3-thioenol ethers and 3-thioacetals of the saturated and unsaturated androstandiones, and then acting an alkyl metallo-organic compound with a member'of the group consisting of the 3-thioen01 ethers and B-thioacetals of the saturated and unsaturated androstandiones, and then hydrolyzing the resultant thio-compound.

5. A process for the manufacture of a member of the group consisting of the 3-thioenol ethers and 3-thioacetals of the saturatedand unsaturated andr0stane-3-one- 17-ois containing hydrocarbon radical in l'l-position, which comprises reacting a methyl magnesium halide with a member of the group consisting of the 3-th-ioenol ethers and 3-thioacetals of the saturated and unsaturated androstandiones, and then hydrolyzing the resultant thio-compound.

6. Aprocess for the manufacture of a member of the group consisting of the 3-thioeno1 ethers and 3-thioacetals of the saturated and unsaturated androstane-3-one-17-ols containing-hydrocarbon radical in 1'7-position, which comprises reacting an unsaturated metallo-organic compound with a member of the group consisting of the 3-thioenol ethers and 3-thioacetals of the saturated and unsaturated androstandiones, and then hydrolyzing the resultant thio-compound.

7. A 3-thioenol ether of an andros'tene-3-one- 17-01 which contains in the l'l-position a member selected from the group consisting orsaturated and unsaturated hydrocarbon radicals.

8. A 3-thioenol ether of an androstene-3-one- 17-01 containing in 17-position an 'alkyl group.

9. A 3-thioenol ether of an androstene-3-one- 17-01 containing in 17-position a methyl group.

10. A 3-thioenol ether of an androstene-3-one- 17-01 containing in 17-position an ethinyl group.

KARL MIESCHER.

REFERENCES CITED The following references are of record in the file of this patent:

Ruzicka, Helv. 'Chim. Acta, v01.- 18 (1935); pages 994998, 1487-1498.

Number Certificate oi Correction Patent No. 2,435,013. January 27, 1948.

KARL MIESGHEE It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column 3, line 9, for the words of dryness read to dryness; column 4, line 7 claim 2, for thiocompound read thz'ocompound; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 6th day of April, A. D. 1948.

THOMAS F. MURPHY,

Assistant Uommz'ssioner 0 f Patents. 

